Development of Thyroid Hormones and Synthetic Thyromimetics in Non-Alcoholic Fatty Liver Disease

Zhao, Man; Xie, Huazhong; Shan, Hong; Zheng, Zhihua; Li, Guofeng; Li, Min; Liu, Hong

doi:10.3390/ijms23031102

Cited by 14 publications

(10 citation statements)

References 141 publications

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“…Previously undetected alterations in several genes revealed novel affected biological processes in response to a low TH state such as cellular proliferation, hypoxia, and oxidative stress, which may serve as hypothesis-generating data for follow-up experiments. We here focused our efforts on lipid metabolism because of the putative role of TH in NAFLD/MASLD regulation [26,27], a condition that also has been linked to circadian rhythms [28,29].…”

Section: Discussionmentioning

confidence: 99%

Tuning of liver circadian transcriptome rhythms by thyroid hormone state in male mice

de Assis,

Harder,

Lacerda

et al. 2023

Preprint

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Thyroid hormones (THs) are important regulators of systemic energy metabolism. In the liver, they stimulate lipid and cholesterol turnover and increase systemic energy bioavailability. It is still unknown how the TH state interacts with the circadian clock, another important regulator of energy metabolism. We addressed this question using a mouse model of hypothyroidism and performed circadian analyses. Low TH levels decreased locomotor activity, food intake, and body temperature mostly in the active phase. Concurrently, liver transcriptome profiling showed only subtle effects compared to elevated TH conditions. Comparative circadian transcriptome profiling revealed alterations in mesor, amplitude, and phase of transcript levels in the livers of low-TH mice. Genes associated with cholesterol uptake, biosynthesis, and bile acid secretion showed reduced mesor. Increased and decreased cholesterol levels in the serum and liver were identified, respectively. Combining data from low- and high-TH conditions allowed the identification of 516 genes with mesor changes as molecular markers of the liver TH state. These genes participate in many known TH-associated processes. We further explored these genes and created a unique expression panel that can assess liver TH state in a time-of-day dependent manner. Our findings suggest that the liver has a low TH state under physiological conditions. Circadian profiling reveals genes as potential markers of liver TH state in one-time point studies.

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Section: Discussionmentioning

confidence: 99%

Tuning of liver circadian transcriptome rhythms by thyroid hormone state in male mice

de Assis,

Harder,

Lacerda

et al. 2023

Preprint

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“…ere are two major isoforms of the thyroid hormone receptor (TR), TRα and TRβ, which are the predominant receptors in the liver [17]. TH metabolites [18], TRβ agonists [19], and liver-specific analogs [20] have been studied as potential therapeutics for treating both serum dyslipidemia and NAFLD. Resmetirom (MGL-3196) and Hep-Direct prodrug VK2809 (MB07811) may be two of the most promising lipidlowering agents currently in phase 2-3 clinical trials [19,21].…”

Section: Discussionmentioning

confidence: 99%

Effect of Liraglutide on Serum TSH Levels in Patients with NAFLD and its Underlying Mechanisms

Wen

et al. 2022

International Journal of Clinical Practice

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This study aimed to evaluate the effect of liraglutide on serum thyroid-stimulating hormone (TSH) levels in patients with type 2 diabetes mellitus (T2DM) and explore the underlying mechanisms via bioinformatics analysis. A total of 49 obese/overweight patients with T2DM received liraglutide during outpatient visits or hospitalization in the Department of Endocrinology. Meanwhile, the control group included 49 patients with T2DM but without nonalcoholic fatty liver disease (NAFLD) who were matched for age and sex (baseline from July 2016 to June 2021). Follow-up data on the last use of liraglutide were also retrieved. Age, sex, body mass index (BMI), and duration of diabetes were obtained from the participants’ records. All patients were tested for biochemical markers hemoglobin A1c (HbA1c), alanine transaminase, aspartate transaminase, free triiodothyronine, free thyroxine (FT4), and TSH at baseline and follow-up. After adjusting for all factors with a p -value < 0.05, BMI, HbA1c, LDL, FT4, and TSH were identified as significant independent risk factors for NAFLD in the univariate analysis. Following liraglutide therapy (average time 16 months), these patients had significantly lower BMI, HbA1c, and TSH but higher high-density lipoprotein (HDL) levels than those in the baseline data (all p < 0.05), and further subgroup analysis stratified by duration of liraglutide use showed that the test for time trends had statistical differences in BMI and TSH but not in HbA1c and HDL. After the therapy, the NAFLD and NASH groups showed significantly decreased TSH levels after liraglutide therapy compared with the corresponding baseline data. Furthermore, the expression of THRB, which encodes TRβ, was significantly decreased in the NAFLD group, which may explain the thyroid hormone resistance-like manifestation in the clinical findings. In conclusion, liraglutide improves hepatic thyroid hormone resistance in T2DM with NAFLD, and restoration of impaired TRβ expression in NAFLD is a potential mechanism involved in the process of liraglutide therapy.

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“…Considering that the TH signaling pathway plays an important role in energy metabolism, researchers have been trying to pharmacologically target the FT3/THR axis for the past few decades. TH metabolites ( 25 ), TRβ agonists ( 26 ), and liver-specific analogs ( 27 ) have been studied as potential therapeutics for treating both serum dyslipidemia and as potential therapies for NAFLD. Resmetirom (MGL-3196) and Hep-Direct prodrug VK2809 (MB07811) probably representing two of the most promising lipid lowering agents, currently under phase 2-3 clinical trials.…”

Section: Discussionmentioning

confidence: 99%

TSH−SPP1/TRβ−TSH positive feedback loop mediates fat deposition of hepatocyte: Crosstalk between thyroid and liver

Huang

Wen

2022

Front. Immunol.

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AimsWe conducted this study with two aims: (1) whether TRβ could be damaged by NAFLD, thereby represent thyroid hormone resistance-like manifestation and (2) to analyze the potential role of SPP1 in TH signaling pathway on the process of NAFLD. This study is expected to provide a new perspective on the therapeutic mechanism in the pathological course of NAFLD.MethodsA total of 166 patients diagnosed with type 2 diabetes mellitus (T2DM) were enrolled in this study. All patients had a BMI above 24 kg/m2 and were stratified into two groups: NAFLD and Non-NAFLD groups. Ages, gender, BMI, duration of diabetes and biochemical markers were obtained from participants’ records. We downloaded the dataset GSE48452 from GEO. The Pathview library was used to make the thyroid hormone signaling pathway visualization. The CIBERSORT algorithm was applied to calculate the infiltrated immune cells in obese NAFLD patients. C57BL/6 mice were randomly selected to constitute the normal control (NC) group and were fed a normal chow diet; the rest of the mice were fed a high-fat diet (HFD). After 12 weeks HFD feeding, the mice were sacrificed by cervical dislocation, and blood samples were collected. Mouse livers were also collected; one part of each liver was fixed in 10% formalin for histological analysis, and the other part was snap-frozen for subsequent molecular analyses. To explore the relationship between SPP1, TRβ and lipid deposition in hepatocytes, HepG2 cells were treated with 50 μ M concentration of PA and/or 20 ng/ml concentration of rh-SPP1 for 48h. In addition, the PC3.1-TRβ plasmid was constructed for further validation in HepG2 cells. We used THP-1 cells to construct an M1 macrophage model in vitro. We then analyzed THP-1 cells treated with various concentrations of PA or TSH.Results(1) After adjusting for all factors that appeared P value less than 0.1 in the univariate analysis, BMI, TSH, and FT3 were significant independent risk factors of NAFLD (ORs were 1.218, 1.694, and 2.259, respectively); (2) A further analysis with BMI stratification indiacted that both FT3 and TSH had a significant change between individuals with NAFLD and Non-NAFLD in obesity subgroup; however, there was no statistic difference in over-weight group; (3) Bioinformatics analysis of GSE48452 had shown that several key molecular (including TRβ) of thyroid hormone pathway affected by NAFLD induced transcriptomic changes and the expression levels of SPP1, FABP4 and RPS4Y1 were significantly higher, while the expression levels of PZP and VIL1 were significantly decreased in NAFLD patients(adjusted p < 0.05, |logFC| > 1.0). The CIBERSORT algorithm showed increased M0 and M1, decreased M2 macrophage infiltration in NAFLD with comparison to healthy obese group; (4) After 12 weeks of HFD-feeding, the obesity mice had significantly higher serum TSH and In IHC-stained liver sections of obesity group, the intensity of SPP1 had a significantly increased, while TRβ reduced; (5) In vitro studies have shown SPP1 aggravated lipid deposition in hepatic cells dependent on down-regulating the expression of TRβ and TSH acts to promote secretion of SPP1 in M1 macrophage cells.ConclusionsSPP1 secretion induced by M1 macrophage polarization, which may down-regulates TRβ in hepatocytes via paracrine manner, on the one hand, the lipid deposition aggravating in liver, on the other hand, a compensatory increase of TSH in serum. The increased TSH can further lead to the following SPP1 secretion of M1 macrophage. The positive feedback crosstalk between thyroid and liver, may be plays an important role in maintaining and amplifying pathological process of NAFLD.

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Development of Thyroid Hormones and Synthetic Thyromimetics in Non-Alcoholic Fatty Liver Disease

Cited by 14 publications

References 141 publications

Tuning of liver circadian transcriptome rhythms by thyroid hormone state in male mice

Tuning of liver circadian transcriptome rhythms by thyroid hormone state in male mice

Effect of Liraglutide on Serum TSH Levels in Patients with NAFLD and its Underlying Mechanisms

TSH−SPP1/TRβ−TSH positive feedback loop mediates fat deposition of hepatocyte: Crosstalk between thyroid and liver

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